The Effects of the Paleo Diet on Autoimmune Thyroid Disease: A Mixed Methods Review.

The aim of this systematic review was to examine the characteristics of Paleolithic diet (PD) interventions designed for adult patients with autoimmune thyroid disease (AITD) in order to determine if diet elements have the potential to successfully reduce thyroid antibodies (Ab) such as thyroglobulin (Tg), thyroid peroxidase (TPO), and thyroid stimulating hormone receptor (TSHR), and improve thyroid hormones (thyroxine (T4), triiodothyronine (T3) and thyroid stimulating hormone (TSH)) or resolve AITD pathogenesis. Randomized controlled trials (RCTs) with an adult population of 18 years and older, diagnosed with Hashimoto's thyroiditis (HT) or Graves' disease (GD) (Basedow's), who were placed on a diet of Paleolithic or ancestral nature, and achieved reduction of AITD Abs, improvement of thyroid hormones, and, or resolution of AITD were searched. Various electronic databases were used. Bias was assessed using critical appraisal tools from the Scottish Intercollegiate Guidelines Network (SIGN) and Joanna Briggs Institute (JBI). Studies were excluded according to exclusion criteria and results analyzed. One randomized controlled trial (RCT), a pilot study, and six case studies were found. In total, eight AITD studies focusing on Paleolithic or ancestral interventions were located. In highlight, females were the predominant gender. Case studies solely focused on AITD with protocols ranging from 8-60 weeks. All studies showed clinical improvements, one had significant improvement, two showed AITD resolution. After structured evaluation of nutritional interventions utilizing the PD on the effects of AITD, it was concluded foods of ancestral nature along with the addition of specific supplements, food components, exercise and mindfulness meditation, and exclusion of modern day foods have a considerable impact on thyroid Ab and hormones. The relevant studies suggest while this dietary protocol can be useful in clinical practice, larger-scale studies need to be conducted. Key teaching pointsThere are currently no dietary interventions recommended for the treatment of autoimmune thyroid disease. The Paleo diet has been documented to improve AITD antibodies and thyroid hormones in both Hashimoto's thyroiditis and Graves' disease.The Paleo diet can provide a natural source of nutrients similar to supplemental nutrients that have shown positive results on AITD.The paleo diet provides specific macronutrient percentages that may be beneficial in reducing AITD antibodies, while improving thyroid hormones.Methylation supplementation may be useful in AITD cases.

Identifying isoniazid resistance markers to guide inclusion of high-dose isoniazid in tuberculosis treatment regimens.

OBJECTIVES: Effective use of antibiotics is critical to control the global tuberculosis pandemic. High-dose isoniazid (INH) can be effective in the presence of low-level resistance. We performed a systematic literature review to improve our understanding of the differential impact of genomic Mycobacterium tuberculosis (Mtb) variants on the level of INH resistance. The following online databases were searched: PubMed, Web of Science and Embase. Articles reporting on clinical Mtb isolates with linked genotypic and phenotypic data and reporting INH resistance levels were eligible for inclusion. METHODS: All genomic regions reported in the eligible studies were included in the analysis, including: katG, inhA, ahpC, oxyR-ahpC, furA, fabG1, kasA, rv1592c, iniA, iniB, iniC, rv0340, rv2242 and nat. The level of INH resistance was determined by MIC: low-level resistance was defined as 0.1-0.4 µg/mL on liquid and 0.2-1.0 µg/mL on solid media, high-level resistance as >0.4µg/mL on liquid and >1.0 µg/mL on solid media. RESULTS: A total of 1212 records were retrieved of which 46 were included. These 46 studies reported 1697 isolates of which 21% (n = 362) were INH susceptible, 17% (n = 287) had low-level, and 62% (n = 1048) high-level INH resistance. Overall, 24% (n = 402) of isolates were reported as wild type and 76% (n = 1295) had ≥1 relevant genetic variant. Among 1295 isolates with ≥1 variant, 78% (n = 1011) had a mutation in the katG gene. Of the 867 isolates with a katG mutation in codon 315, 93% (n = 810) had high-level INH resistance. In contrast, only 50% (n = 72) of the 144 isolates with a katG variant not in the 315-position had high-level resistance. Of the 284 isolates with ≥1 relevant genetic variant and wild type katG gene, 40% (n = 114) had high-level INH resistance. CONCLUSIONS: Presence of a variant in the katG gene is a good marker of high-level INH resistance only if located in codon 315.

Impairment of sperm maturation and capacitation due to diet-dependent cholesterol overload.

BACKGROUND: Lipid metabolic disorders (dyslipidemia) are constantly increasing in occidental societies and lead to the development of pathologies such as obesity, diabetes, and metabolic syndrome. It has been demonstrated that dyslipidemia can alter the reproductive function. Animal models have recently been used to show that the offspring of dyslipidemic males could also develop such pathologies and that the transgenerational transmission involved post-testicular sperm maturation. These data targeted the essential role of male gamete epididymal maturation and its importance for the health of the offspring. OBJECTIVES: This publication summarizes in the first place experimental data obtained using a mouse model of dyslipidemia-induced post-testicular infertility, knockout mice for the two isoforms of the 'Liver X Receptors' (Lxrα;ß-/- ), the major regulators of cholesterol homeostasis. The impact of a high cholesterol diet (HCD) on the protein YWHAZ (14-3-3 ζ or tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein Zeta) was also investigated in our model. MATERIALS AND METHODS: In our mouse model, when young fertile Lxrα;ß-/- males aged three months were fed four weeks with a HCD, they developed an epididymal phenotype leading to infertility. The level of sperm YWHAZ was evaluated by Western blot and its tyrosine phosphorylation state by immunoprecipitation followed by Western blot. RESULTS: Our data revealed that sperm lipid composition and structure were altered, leading to defects of the capacitation-associated signaling pathway. They also showed that both the level and the tyrosine phosphorylation state of YWHAZ were affected by the HCD in sperm cells from Lxrα;ß-/- males. DISCUSSION AND CONCLUSION: YWHAZ could be a new important regulator of capacitation-associated tyrosine phosphorylation and a marker of dyslipidemia-induced infertility.

Evaluation of a novel line probe assay to detect resistance to pyrazinamide, a key drug used for tuberculosis treatment.

OBJECTIVES: The development of rapid molecular diagnostic assays for pyrazinamide (PZA) resistance is considered technically challenging as mutations are highly diverse, scattered along the full length of the pncA gene and not all are associated with PZA resistance. We evaluated the performance of the novel Genoscholar PZA-TB II line probe assay (PZA-LPA2; NIPRO Corporation, Japan). METHODS: To evaluate the applicability of the PZA-LPA2 in clinical settings, we compared the performance of the PZA-LPA2 to a composite reference standard pncA Sanger and Illumina sequencing plus phenotypic susceptibility testing on a panel of 87 Mycobacterium tuberculosis isolates from World Health Organization (WHO) drug resistance surveys, harbouring mutations previously classified as associated or not associated with resistance according to data from peer-reviewed literature. In addition, the PZA-LPA2 was challenged against a selection of isolates with lineage-specific and non-resistance-associated mutations, for which the frequency among clinical isolates is unknown, and tested directly on 59 sputum extracts. RESULTS: For the survey isolates, the PZA-LPA2 reached an overall agreement with the composite reference of 97.6% (80/82) or 94.3% (82/87) excluding or including heteroresistance, respectively. The PZA-LPA2 failed on 8.5% (5/59) of clinical samples; among valid results, 100% (14/14) sensitivity and 100% (7/7) specificity was reached relative to pncA Sanger sequencing. CONCLUSIONS: The PZA-LPA2 represents a valid and rapid alternative for indirect PZA susceptibility testing. Preliminary findings on clinical samples show promise for direct testing. Further studies are needed to assess the clinical risk of missing heteroresistance and falsely detecting lineage-specific, silent and nonassociated mutations.

Dyslipidemia alters sperm maturation and capacitation in LXR-null mice.

Lipid metabolism disorders (dyslipidemia) are causes of male infertility, but little is known about their impact on male gametes when considering post-testicular maturation events, given that studies concentrate most often on endocrine dysfunctions and testicular consequences. In this study, three-month-old wild-type (wt) and Liver-X-Receptors knock out (Lxrα;ß-/- ) males were fed four weeks with a control or a lipid-enriched diet containing 1.25% cholesterol (high cholesterol diet (HCD)). The HCD triggered a dyslipidemia leading to sperm post-testicular alterations and infertility. Sperm lipids were analyzed by LC-MS and those from Lxrα;ß-/- males fed the HCD showed higher chol/PL and PC/PE ratios compared to wt-HCD (P < 0.05) and lower oxysterol contents compared to wt (P < 0.05) or Lxrα;ß-/- (P < 0.05). These modifications impaired membrane-associated events triggering the tyrosine phosphorylation normally occurring during the capacitation process, as shown by phosphotyrosine Western blots. Using flow cytometry, we showed that a smaller subpopulation of spermatozoa from Lxrα;ß-/- -HCD males could raise their membrane fluidity during capacitation (P < 0.05 vs wt or wt-HCD) as well as their intracellular calcium concentration (P < 0.05 vs Lxrα;ß-/- and P < 0.001 vs wt). The accumulation of the major sperm calcium efflux pump (PMCA4) was decreased in Lxrα;ß-/- males fed the HCD (P < 0.05 vs Lxrα;ß-/- and P < 0.001 vs wt). This study is the first showing an impact of dyslipidemia on post-testicular sperm maturation with consequences on the capacitation signaling cascade. It may lead to the identification of fertility prognostic markers in this pathophysiological situation, which could help clinicians to better understand male infertilities which are thus far classified as idiopathic.

Long-term outcome after neonatal intraparenchymal echodensities with porencephaly.

OBJECTIVE: To compare long-term neurodevelopmental and functional outcomes of neonatal intensive care unit (NICU) survivors with neonatal intraparenchymal echodensities (IPE) with porencephaly on cranial ultrasonography with matched controls. To compare the developmental trajectories of these infants over the childhood years with those of matched controls. DESIGN: Cohort study. SETTING: Tertiary level NICU and the Neonatal Follow-Up Programme (NFUP) in Vancouver, Canada. PATIENTS: NICU survivors with birth weights <1250 g, born between 1983 and 1985. METHODS: Cranial ultrasound scans of NICU subjects with grade 4 intraventricular haemorrhage (IVH) were reviewed by a neuroradiologist and cases were defined, using stringent criteria, as IVH with IPE with porencephaly. Controls with normal cranial ultrasound findings were selected case-matched for birth weight and sex. Prospective sequential multidisciplinary assessments were performed up to 17 years in the NFUP. Mann-Whitney U test was used to compare outcomes between cases and controls. RESULTS: Of 385 eligible patients, 14 met IPE and porencephaly criteria and 10 survived to discharge. All cases with IPE and porencephaly had one or more impairments, significantly different from preterm controls (p<0.001). At all ages assessed, rates of motor, cognitive and overall impairment were significantly higher in the cases (p< or =0.002 for all tests). Most cases at adolescence were ambulatory, required learning assistance in school and had social challenges. CONCLUSIONS: Children with neonatal IPE and porencephaly have a much worse long-term neurodevelopmental outcome than children with normal cranial ultrasound findings.

Magnetoencephalography study of brain dynamics in young children born extremely preterm.

Magnetoencephalography (MEG) was recorded while 5-7 year-old children were performing a visual-spatial memory recognition task. Full-term children showed greater gamma-band (30-50 Hz) amplitude in the right temporal region during the task, than children who were born extremely preterm. These results may represent altered brain processing in extremely preterm children who escape major impairment.

Assessment of internet use and effects among healthcare professionals: a cross sectional survey.

PURPOSE: Several studies have explored the scientific platforms on patient use of the internet for health information. In contrast physicians' perspective on evolving internet environment is lacking. The purpose of this study is to assess and correlate the extent of internet use among healthcare professionals and examine its effects on clinical practice. METHODS: Cross sectional survey conducted in the USA using questionnaires distributed randomly to healthcare professionals attending distinct continuing medical education programmes between 2003 and 2004. Multiple choice and yes/no questions related to the trends of internet use and its effects on clinical practice were extracted and responses analysed. The main outcome measures are self reported rates of internet use, perceived effects, and the role of medical web sites in clinical practice. RESULTS: The overall response rate was 60%. A total of 277 survey respondents (97%) had internet access. Some 7% in private practice and 1% of group practice physicians did not have internet access. Most (71%) used the internet regularly for medical or professional updating and 62% (n = 178) felt the need for sharing web sites designed for healthcare professionals with patients. Some 27% of the physicians currently own established personal practice web sites. Sixty three per cent have recommended a web site to a patient for more information, matching the positive trust (>70%) on the general quality of selected medical web sites. CONCLUSION: This cross sectional survey shows that internet use and web based medical information is widely popular among physicians and patients. About 23%-31% of the healthcare professionals report >80% interaction with web informed patients in their daily practice.

Demographic and therapeutic determinants of pain reactivity in very low birth weight neonates at 32 Weeks' postconceptional Age.

BACKGROUND: Management of pain in very low birth weight infants is limited by a lack of empiric knowledge about the multiple determinants of biobehavioral reactivity in infants receiving neonatal intensive care. OBJECTIVE: To examine relationship of early neonatal factors and previous medication exposure to subsequent biobehavioral reactivity to acute pain of blood collection. DESIGN: Prospective cohort study. Methods. One hundred thirty-six very low birth weight (

Relations between behavioral and cardiac autonomic reactivity to acute pain in preterm neonates.

OBJECTIVE: The purpose of this study was to assess relations and concordance between behavioral and physiologic reactivity to pain in preterm neonates at 32 weeks postconceptional age as a function of gestational age at birth. SETTING: Level III neonatal intensive care unit. DESIGN/PATIENTS: The study group comprised 136 preterm neonates (mean [range] birthweight, 1,020 g [445-1,500 g]: gestational age at birth, 28 weeks [23-32 weeks]) separated into three groups according to gestational age at birth as follows: 23 to 26 weeks (n = 48), 27 to 29 weeks (n = 52), and 30 to 32 weeks (n = 36). OUTCOME MEASURES: Reactivity to routine blood collection at 32 weeks postconceptional age was assessed using bedside-recorded behavioral and autonomic measures. Coders who were blinded to the study design scored behavioral responses (facial activity using the Neonatal Facial Coding System, sleep/waking state, and finger splay). Autonomic reactivity was assessed by change in heart rate and spectral analysis of heart rate variability (change in low-frequency and high-frequency power, and the ratio of low-frequency to high-frequency power during blood collection). RESULTS: Facial activity and state correlated moderately with change in heart rate across gestational age groups (r = 0.41-0.62). Facial activity and state did not correlate significantly with change in low-frequency and high-frequency power, or the ratio of low-frequency to high-frequency power (r = 0.00-0.31). Finger splay did not correlate with any autonomic recording (r = 0.03-0.41). Concordance between established biobehavioral measures of pain revealed individual differences. Although some neonates showed high behavioral but low physiologic reactivity, other neonates displayed the opposite reaction; however, the majority displayed concordant reactions. CONCLUSIONS: The study findings confirm the value of measuring domains independently, especially in neonates born at a very young gestational age.

Characterization of the histone H1-binding protein, NASP, as a cell cycle-regulated somatic protein.

Nuclear autoantigenic sperm protein (NASP), initially described as a highly autoimmunogenic testis and sperm-specific protein, is a histone-binding protein that is a homologue of the N1/N2 gene expressed in oocytes of Xenopus laevis. Here, we report a somatic form of NASP (sNASP) present in all mitotic cells examined, including mouse embryonic cells and several mouse and human tissue culture cell lines. Affinity chromatography and histone isolation demonstrate that NASP from myeloma cells is complexed only with H1, linker histones. Somatic NASP is a shorter version of testicular NASP (tNASP) with two deletions in the coding region arising from alternative splicing and differs from tNASP in its 5' untranslated regions. We examined the relationship between NASP mRNA expression and the cell cycle and report that in cultures of synchronized mouse 3T3 cells and HeLa cells sNASP mRNA levels increase during S-phase and decline in G(2), concomitant with histone mRNA levels. NASP protein levels remain stable in these cells but become undetectable in confluent cultures of nondividing CV-1 cells and in nonmitotic cells in various body tissues. Expression of sNASP mRNA is regulated during the cell cycle and, consistent with a role as a histone transport protein, NASP mRNA expression parallels histone mRNA expression.

Behavior, pain perception, and the extremely low-birth weight survivor.

This article explores the literature concerning responses to pain of both premature and term-born newborn infants, the evidence for short-term and long-term effects of pain, and behavioral sequelae in individuals who have experienced repeated early pain in neonatal life as they mature. There is no doubt that pain causes stress in babies and this in turn may adversely affect long-term neurodevelopmental outcome. Although there are methods for assessing dimensions of acute reactivity to pain in an experimental setting, there are no very good measures available at the present time that can be used clinically. In the clinical setting repeated or chronic pain is more likely the norm rather than infrequent discrete noxious stimuli of the sort that can be readily studied. The wind-up phenomenon suggests that, exposed to a cascade of procedures as happens with clustering of care in the clinical setting in an attempt to provide periods of rest for stressed babies, an infant may in fact perceive procedures that are not normally viewed as noxious, as pain. Pain exposure during lifesaving intensive medical care of ELBW neonates may also affect subsequent reactivity to pain in the neonatal period, but behavioral differences are probably not likely to be clinically significant in the long term. Prolonged and repeated untreated pain in the newborn period, however, may produce a relatively permanent shift in basal autonomic arousal related to prior NICU pain experience, which may have long-term sequelae. In the long run, the most significant clinical effects of early pain exposure may be on neurodevelopment, contributing to later attention, learning, and behavior problems in these vulnerable children. Although there is considerable evidence to support a variety of adverse effects of early pain, there is less information about the long-term effects of opiates and benzodiazepines on the developing central nervous system. Current evidence reviewed suggests that judicious use of morphine for adjustment to mechanical ventilation may ameliorate the altered autonomic response. It may be very important, however, to distinguish stress from pain. Animal evidence suggests that the neonatal brain is affected differently when exposed to morphine administered in the absence of pain than in the presence of pain. Pain control may be important for many reasons but overuse of morphine or benzodiazepines may have undesirable long-term effects. This is a rapidly evolving area of knowledge of clear relevance to clinical management likely to affect long-term outcomes of high-risk children.

Stem-loop binding protein, the protein that binds the 3' end of histone mRNA, is cell cycle regulated by both translational and posttranslational mechanisms.

The expression of the replication-dependent histone mRNAs is tightly regulated during the cell cycle. As cells progress from G(1) to S phase, histone mRNA levels increase 35-fold, and they decrease again during G(2) phase. Replication-dependent histone mRNAs are the only metazoan mRNAs that lack polyadenylated tails, ending instead in a conserved stem-loop. Much of the cell cycle regulation is posttranscriptional and is mediated by the 3' stem-loop. A 31-kDa stem-loop binding protein (SLBP) binds the 3' end of histone mRNA. The SLBP is necessary for pre-mRNA processing and accompanies the histone mRNA to the cytoplasm, where it is a component of the histone messenger RNP. We used synchronous CHO cells selected by mitotic shakeoff and HeLa cells synchronized at the G(1)/S or the M/G(1) boundary to study the regulation of SLBP during the cell cycle. In each system the amount of SLBP is regulated during the cell cycle, increasing 10- to 20-fold in the late G(1) and then decreasing in the S/G(2) border. SLBP mRNA levels are constant during the cell cycle. SLBP is regulated at the level of translation as cells progress from G(1) to S phase, and the protein is rapidly degraded as they progress into G(2). Regulation of SLBP may account for the posttranscriptional component of the cell cycle regulation of histone mRNA.

Are twitches, startles, and body movements pain indicators in extremely low birth weight infants?

OBJECTIVE: The goal of this study was to examine whether body activity such as postural, trunk, and limb movements may be potential pain cues in preterm infants. DESIGN: Convenience sample. SETTING: Level III neonatal intensive care unit (NICU). PATIENTS: Extremely low birth weight (< or = 1,000 g) preterm infants (n = 64) undergoing routine NICU medical care. OUTCOME MEASURES: Procedures likely to differ in evoking distress (i.e., endotracheal suctioning, chest physical therapy, diaper change, or nasogastric feed) were observed. Behaviors were recorded at bedside using the Neonatal Individualized Developmental Care and Assessment Program system. RESULTS: Changes in heart rate and sleep/waking state were related to the procedures, supporting the assumption of differing relative disruption to the infant. Arching, squirming, startles, and twitching were not observed significantly more during procedures than at baseline. After controlling for background variables, finger splay and leg extension were significantly related to ongoing procedures. Facial brow raising was a function of the number of invasive procedures in the past 24 hours; thus, it may be a useful cue of sensitization. CONCLUSIONS: Some extensor movements seemed to be distress signals, whereas tremors, startles, and twitches were not related to discomfort during the observation period. These behaviors may differ qualitatively during longer lasting tissue invasive events. The results of this study indicate the need for more in-depth study of patterns of motor activity in preterm infants over longer observation periods to evaluate potential signs of stress and pain in babies undergoing NICU medical care.

Biobehavioral pain responses in former extremely low birth weight infants at four months' corrected age.

OBJECTIVE: To compare biobehavioral responses to acute pain at 4 months' corrected age between former extremely low birth weight (ELBW) infants and term-born controls. METHODOLOGY: Measures of facial behavioral and cardiac autonomic reactivity in 21 former ELBW infants (mean birth weight = 763 g) were compared with term-born infants (n = 24) during baseline, lance, and recovery periods of a finger-lance blood collection. Further, painful procedures experienced during neonatal care were quantified in both groups. RESULTS: Overall, behavioral and cardiac autonomic responses to the lance were similar between groups. However, the ELBW group seemed to have a less intense parasympathetic withdrawal in the lance period and a more sustained sympathetic response during recovery than the control group. Further, in the recovery period, two behavioral patterns (early recovery and a late recovery) were apparent among the ELBW group. CONCLUSIONS: Biobehavioral pain responses were similar overall between both groups of infants. Subtle differences were observed in cardiac autonomic responses during the lance period and in behavioral recovery among ELBW infants. Whether these findings represent a long-term effect of early pain experience or a developmental lag in pain response remains unclear. The lack of an overall difference runs counter to previously reported findings of reduced behavioral response in former ELBW infants. biobehavioral pain response, premature infants, repetitive pain, heart rate variability.

Predicting IQ of biologically "at risk" children from age 3 to school entry: sensitivity and specificity of the Stanford-Binet Intelligence Scale IV.

Predictive validity of the Stanford-Binet Intelligence Scale Fourth Edition (S-B IV) from age 3 years to ages 4-5 years was evaluated with biologically "at risk" children without major sensory or motor impairments (n = 236). Using the standard scoring, children with full scale IQ < or = 84 on the Wechsler Preschool and Primary Scale of Intelligence at age 4-5 years were poorly identified (sensitivity 54%) from the composite S-B IV score at age 3. However, sensitivity improved greatly to 78% by including as a predictor the number of subtests the child was actually able to perform at age 3 years. Measures from the Home Screening Questionnaire and ratings of mother-child interaction further improved sensitivity to 83%. The standard method for calculating the composite score on the S-B IV excludes subtests with a raw score of 0, which overestimates cognitive functioning in young biologically high risk children. Accuracy of early identification was improved significantly by considering the number of subtests the child did not perform at age 3 years.

How effective are prevention strategies in reducing the prevalence of pressure ulcers?

The prevalence of pressure ulcers has remained constant at about 7% over the past 20 years, even though considerable time and money has been invested in various prevention strategies. This literature review explores whether pressure-prevention programmes can reduce the prevalence rate still lower or whether they are working but are limited by an increasingly aged population and rising patient acuity.